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Sulodexide for use in the treatment of pathologies wherein metalloproteinases are involved

Active Publication Date: 2013-02-21
ALFASIGMA SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new medication called sulodexide that can be used to treat diseases caused by an increase in a specific enzyme called MMP-9. This medication can be taken by mouth or injected into a vein or muscle, and can be given in high doses without causing any side effects. Compared to other drugs in the market, sulodexide is more selective toward MMP-9, has fewer side effects, and is more easily tolerated.

Problems solved by technology

Clinical trials executed with the available compounds have shown that prolonged treatments cause muscular-skeletal pain and inflammation.
Although these events showed to be reversible and the patients started again the treatment after a short suspension period, the unexpected adverse events have limited the administration dosages.
Moreover, when the clinical trials for the treatment of neoplastic diseases were extended to a greater number of patients, besides serial toxicological problems due to the cytostatic effects, no significant therapeutic benefit was observed, as described by Mannello F. et al. in Curr.
Batimastat is a powerful inhibitor of MMPs and has been the first inhibitor of MMP used in clinical trials, but it has shown low selectivity caused by low solubility and absorption.
As a consequence, it is not possible to know if the concentration of lithium heparin, which provided the effect observed, might be therapeutically useful, being well known the high risk of bleeding associated to HMWH.

Method used

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  • Sulodexide for use in the treatment of pathologies wherein metalloproteinases are involved
  • Sulodexide for use in the treatment of pathologies wherein metalloproteinases are involved
  • Sulodexide for use in the treatment of pathologies wherein metalloproteinases are involved

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0139]Process to Obtain Dermatan Sulfate Fraction from Sulodexide

[0140]A quantity of sulodexide extracted from intestinal animal mucosa, corresponding to 8 mg was dissolved in a binding buffer constituted by TRIS 50 mM and NaCl 50 mM at pH 7.4, and loaded on an affinity column prepared by coupling 7.5 mg of ATIII / ml of CNBr-activated Sepharose gel (GE).

[0141]The column was washed with the same buffer solution and the absorbed material was eluted with a buffer solution consisting of TRIS 50 mM, NaCl 3M at pH 7.4.

[0142]Dermatan sulfate fraction was collected in the non absorbed material present in the flow-through, while heparin fraction, is collected in the eluted fractions.

[0143]Dermatan sulfate and heparin fraction could be stored at −20° or optionally lyophilized.

[0144]Heparin pooled fractions and dermatan sulfate pooled fractions were analyzed in gel permeation chromatography (GPC) and in agarose gel.

[0145]Chromatographic profiles were obtained in HPLC system HP 1090, equipped wi...

example 2

[0151]Effect of sulodexide on circulating MMPs in blood samples

[0152]Samples of blood collected from 50 healthy volunteers, 25 female and 25 male of age between 25 and 58, average age of 37 years, were placed in test tubes and two sets of samples were prepared; in the first set were added variable amount of sulodexide until to obtain final concentration corresponding to 0, 12, 24, 48 μg / ml, in the second set were added variable amounts of dermatan obtained as in Example 1, up to the final concentration corresponding to 0, 2.5, 5, and 10 μg / ml. The samples without the addition of sulodexide and dermatan were used as control and the bands of MMPs, of these samples were attributed the arbitrary value of intensity of 100%. The intensity of the MMPs bands of the treated samples were reported as percentage in respect to the untreated samples.

[0153]Overall samples were centrifuged at 1550 g for 10 minutes at 4° C., an amount of supernatants of serum samples (S) corresponding to 150 μg of t...

example 3

[0158]Effect of Sulodexide on the Amounts of Circulating MMPs in the Plasma

[0159]Samples of blood are collected from 50 healthy volunteers, 25 female and 25 male of age between 25 and 58, average age of 37, and 1 ml of each sample is added to 38 μl of a solution of sodium citrate 0.13 M and centrifuged at 1550 g for 10 minutes at 4° C.

[0160]Increased amounts of sulodexide are added to the samples up to obtain final concentration corresponding respectively to 0, 12, 24 and 48 μg / ml.

[0161]An amount corresponding to 150 μg of total proteins of supernatants of plasma samples (P) obtained by centrifugation, measured through Bradford method, is analyzed by zymography-gelatin. The standard of gelatinase, prepared diluting the capillary blood from healthy volunteers by 15 volumes of Laemmli buffer, in non reducing conditions, are loaded in the gel.

[0162]The gelatin-zymograms and the electrophoresis rune are executed as described in Example 2.

[0163]The zymograms areas of the band are determi...

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Abstract

The present invention describes sulodexide or at least one of its components for use in the reduction of circulating matrix metalloproteinase (MMPs), in particular MMP-9. Sulodexide and its composition are useful for the treatment of pathologies wherein the MMPs are involved, such as cardiovascular disease, cardiovascular disease caused by diabetes, varicose veins, chronic venous insufficiency (CVI), gastrointestinal ulcers, pulmonary disease, and neoplastic pathologies.

Description

[0001]The present invention describes sulodexide, or at least one of its components for use in the reduction of circulating matrix metalloproteinase (MMPs), in particular MMP-9.[0002]Sulodexide and its composition are useful for the treatment of pathologies wherein the MMPs are involved, such as cardiovascular disease, cardiovascular disease caused by diabetes, varicose veins, chronic venous insufficiency (CVI), gastrointestinal ulcers, pulmonary disease, and neoplastic pathologies.BACKGROUND OF THE INVENTION[0003]Recent studies have demonstrated the involvement of a group of zinc-dependent endopeptidases, called matrix metalloproteinase (MMPs), belonging to the matrixin family in the vascular alteration of cardiovascular pathologic conditions.[0004]Venous hypertension is at the basis of several pathologies related to disorders of macro and micro circulation disorders and causing infiltrations of leucocytes in the endothelium, deterioration of the cardiac valves and finally providin...

Claims

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Application Information

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IPC IPC(8): A61K31/737A61P31/00A61P35/00C08B37/10A61P9/00A61P9/10C08B37/00A61K31/727A61P1/04
CPCA61K31/737A61K2300/00A61P1/04A61P31/00A61P35/00A61P7/02A61P9/00A61P9/10A61P9/14A61K31/727A61K35/38A61K47/00
Inventor VISCOMI, GIUSEPPE CLAUDIOMANNELLO, FERDINANDOBRUNO, CRISTIANA
Owner ALFASIGMA SPA
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